The Circadian Clock Gene Bmal1 Regulates Microglial Pyroptosis After Spinal Cord Injury via NF‐κB/MMP9

• DOI: 10.1111/cns.70130
• Publication Date: 2024-12-09T07:35:13Z
• Authors: Dachuan Li; Siyang Liu; Xiao Lu; Zhaoyang Gong; Hongli Wang; Xinlei Xia; Feizhou Lu; Jianyuan Jiang; Yuxuan Zhang; Guangyu Xu; Fei Zou; Xiaosheng Ma
• Keywords: 0301 basic medicine; 03 medical and health sciences; Original Article

ABSTRACTBackgroundThe treatment of spinal cord injury (SCI) is usually ineffective, because neuroinflammatory secondary injury is an important cause of the continuous development of spinal cord injury, and microglial pyroptosis is an important step of neuroinflammation. Recently, Bmal1, a core component of circadian clock genes (CCGs), has been shown to play a regulatory role in various tissues and cells. However, it is still unclear whether Bmal1 regulates microglial pyroptosis after SCI.MethodsIn this study, we established an in vivo mouse model of SCI using Bmal1 knockout (KO) mice and wild‐type (WT) mice, and lipopolysaccharide (LPS)‐induced pyroptosis in BV2 cells as an in vitro model. A series of molecular and histological methods were used to detect the level of pyroptosis and explore the regulatory mechanism in vivo and in vitro respectively.ResultsBoth in vitro and in vivo results showed that Bmal1 inhibited NLRP3 inflammasome activation and microglial pyroptosis after SCI. Further analysis showed that Bmal1 inhibited pyroptosis‐related proteins (NLRP3, Caspase‐1, ASC, GSDMD‐N) and reduced the release of IL‐18 and IL‐1β by inhibiting the NF‐κB /MMP9 pathway. It was important that NF‐κB was identified as a transcription factor that promotes the expression of MMP9, which in turn regulates microglial pyroptosis after SCI.ConclusionsOur study initially identified that Bmal1 regulates the NF‐κB /MMP9 pathway to reduce microglial pyroptosis and thereby reduce secondary spinal cord injury, providing a new promising therapeutic target for SCI.